Morphine therapy

ABSTRACT

A bilayer comprising a morphine layer of morphine, poly(alkylene oxide) and poly(vinylpyrrolidone); and an expandable contacting layer of coated granules of a higher molecular weight poly(alkylene oxide) and a hydroxyalkylcellulose, which bilayer is disclosed for morphine therapy. A method is disclosed for using the bilayer composition.

FIELD OF THE INVENTION

This invention pertains to a novel therapeutic composition of mattercomprising morphine. This invention also concerns a novel dosage formcomprising morphine. This invention additionally relates to a method ofadministering the therapeutic composition comprising morphine to producean analgesic effect. The invention further relates to a method ofadministering the dosage form for delivering morphine to produce ananalgesic effect.

BACKGROUND OF THE INVENTION

Morphine is a potent narcotic analgesic which is principally used torelieve pain. Morphine is used also in the management of dyspnea ofheart failure, in pulmonary edema and cough, as a sedative, and in thecontrol of diarrhea. Morphine most significant actions are analgesic,hypnosis, respiratory depression, central nervous system depressanteffects, and as a local anesthetic. Morphine is administered effectivelyby injection, but a pharmaceutically acceptable material means foradministering morphine orally as an analgesic, as an adjunct toanesthesia, as an antitussine, and a nonspecific antidiarrheal therapyappears to be lacking in the pharmaceutical and medical arts.

SUMMARY OF THE INVENTION

In view of the foregoing, it is apparent that a serious need exists foran improved delivery of morphine for its therapeutic effects. Thus, itis an object of the present invention to provide a novel therapeuticcomposition comprising morphine, and a novel dosage form comprisingmorphine, which therapeutic composition, or dosage form in bothinventions provides a novel method of administering morphine for itsintended therapy. The invention provides a novel and unique means ofmorphine administration when compared to intramuscular, subcutaneous,and intravenous administration.

DETAILED DESCRIPTION OF THE INVENTION

The drug morphine as embraced by this invention comprises (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol. Representativeof morphines for this invention comprise a member selected from thegroup consisting of morphine base, morphine pharmaceutically acceptablesalt, pharmaceutically acceptable inorganic salt, pharmaceuticallyacceptable organic salt, morphine hydrobromide, morphine hydrochloride,morphine mucate, morphine N-oxide, morphine sulfate, morphine acetate,morphine phosphate dibasic, morphine phosphate monobasic, morphineinorganic salt, morphine organic salt, morphine acetate trihydrate,morphine bi(heptafluorobutyrate), morphine bi(methylcarbamate), morphinebi(pentafluoropropionate), morphine bi(pyridine-3-carboxylate), morphinebi(trifluoroacetate), morphine bitartrate, morphine chlorhydrate, andmorphine sulfate pentahydrate.

EXAMPLE 1

A novel therapeutic composition comprising morphine, wherein morphine isa member selected from the group consisting of morphine and morphinepharmaceutically acceptable salt is prepared as follows: first, 432 g ofmorphine sulfate pentahydrate, 963 g of poly(alkylene oxide) comprisinga 300,000 molecular weight and 90 g of poly(vinyl pyrrolidone) having anaverage molecular weight of 40,000 are added to a mixing bowl and drymixed for 10 to 12 minutes. Next, 404 g of denatured, anhydrous alcoholis slowly added to the blended composition-forming materials withcontinuous mixing for 15 minutes. Then, the prepared wet granulation ispassed through a 20 mesh screen, and allowed to dry at room temperatureof 25° C. for 18 hours, and then passes through a 16 mesh screen. Thescreened granulation is transferred to a planetary mixer, and withconstant blending 14.9 g of calcium stearate is added to produce thetherapeutic composition. The composition is compressed into tabletcomprising 250 mg of the therapeutic composition consisting of 70 mg ofmorphine sulfate. The tablets are compressed under 10 tons of pressureto provide sustained-release morphine sulfate tablet.

EXAMPLE 2

A therapeutic composition provided by this invention comprises 50 ng to1200 mg of a member selected from the group consisting of morphine,morphine base, morphine salt, and morphine derivative; 5 mg to 750 mg ofa poly(alkylene oxide) comprising a 100,000 to 650,000 molecular weightand selected from the group consisting of poly(methylene oxide),poly(ethylene oxide), poly(propylene oxide), poly(isopropylene oxide),and poly(butylene oxide); 0.5 mg to 80 mg of poly(vinyl pyrrolidone)having a 3,000 to 350,000 average molecular weight; and 0 to 10 mg of alubricant represented by a member selected from the group consisting ofmagnesium stearate, calcium stearate, potassium oleate, stearic acid,and sodium stearate. The therapeutic composition may contain othercomponents for examples colurants, compression aids, and binders. Thecomposition can be compressed at 1/8 to 10 ton-force, to yield anorally-administrable tablet comprising morphine sulfate.

The therapeutic composition can be dry compressed into an orallyadministrable tablet. For example, a mixture of dry-powder ingredientscomprising morphine pharmaceutically acceptable base, or morphinepharmaceutically acceptable salt represented by hydrochloride,hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate,laureate, borate, benzoate, lactate, phosphate, tosylate, titrate,maleate, fumarate, succinate, tartrate and napsylate; a tablet excipientrepresented by 0 to 750 mg of microcrystalline cellulose, and 5 to 750mg of a carboxymethylcellulose such as sodium carboxymethylcellulose of10,000 to 800,000 molecular weight; a binding agent represented bypoly(vinyl pyrrolidone), hydroxypropylcellulose andhydroxypropylmethylcelluylose and gelatin; and a lubricant like stearicacid, calcium stearate, and magnesium stearate, are dried sieved andmixed with other optional components such as a surfactant and flavoringagent fed to a tablet press and the mixture compressed under force toyield dry-compressed morphine tablets for oral administration. In anoptional manufacture provided by this invention, a therapeuticcomposition made by wet granulation or dry granulation techniques can besurrounded with a semipermeable polymeric wall comprising a celluloseacylate and an exit means for delivering morphine at acontrolled-sustained rate of delivery through the exit means over time.

EXAMPLE 3

A dosage form is provided by the invention by first preparing a morphinecomposition wherein 1728 g of morphine sulfate pentahydrate, 3852 g ofpoly(ethylene oxide) possessing a 200,000 molecular weight, and 360 g ofpoly(vinyl pyrrolidone) having an average molecular weight of 40,000 areadded to a planetary mixing bowl. Next, the dry materials were mixed forten minutes. Then, 1616 g of denatured anhydrous ethyl alcohol is slowlyadded to the blended materials with continuous mixing for 15 minutes.Next, the freshly prepared wet granulation was passed through a 20 meshscreen, allowed to dry at room temperature for 20.5 hours, and passedthrough a 16 mesh screen. Next, the granulation was transferred to aplanetary mixer, mixed and lubricated with 59.8 g of magnesium stearate.

Next, a push composition is prepared as follows: first a binder solutionwas prepared dry dissolving 3910 g of hydroxypropylmethylcellulosepossessing an average molecular weight of 11,200 in 45,339 g of water.Next, 101 g of butylated hydroxytoluene was dissolved in 650 g ofdenatured anhydrous alcohol. Approximately 2.5 kg of thehydroxypropylmethylcellulose/water solution is added to the butylatedhydroxytoluene/alcohol solution with continuous mixing. Next, the bindersolution preparation is completed by adding the remaininghydroxypropylmethylcellulose/water solution to the butylatedhydroxytoluene/alcohol solution, again with continuous mixing.

Next, 36,000 g of sodium chloride was sized using a Quadro Comil® mill,used to reduce the particle size of the sodium chloride. A fluid airmill is another mill used to size materials with a 21 mesh screen. Next,1200 g of ferric oxide was passed through a 40 mesh screen. Then, allthe screened materials, 76,400 g of pharmaceutically acceptablepoly(ethylene oxide) comprising a 7,000,000 molecular weight, 2520 g ofhydroxypropylmethylcellulose comprising an average molecular weight of11,200 are added to a Glatt Fluid Bed Granulator's bowl. The bowl wasattached to the granulator and the granulation process was initiated foreffecting granulation. Next, the dry powders were air suspended andmixed for 10 minutes. Then, the binder solution was sprayed from 3nozzles onto the powder. The granulating conditions were monitoredduring the process as follows: total solution spray rate of 800 g/rain;inlet temperature 43° C.; and process air flow of 4300 m³ /hr.

While spraying the binder solution, the filter bags were shaken for 10seconds every 1.5 minutes to unglue any possible powder deposits. At theend of the solution spraying, 45,033 g, the coated granulated particleswere continued with the drying process for 35 minutes. The machine wasturned off, and the coated granules were removed from the granulator.The coated granules were sized using a Quadro Comil with an 8 meshscreen. The granulation was transferred to Tote Tumbler, mixed andlubricated with 281.7 g of magnesium stearate.

Next, the morphine sulfate pentahydrate drug composition and the pushcomposition are compressed into bilayer tablets on the Kilian® TabletPress. First, 434 mg of the morphine sulfate pentahydrate composition isadded to the die cavity and pre-compressed, then, 260 mg of the pushcomposition is added and the layers are pressed under a pressure head ofapproximately 3 metric tons into a 0.700" (1.78 cm)×0.375" (0.95 cm)oval contacting layered arrangement.

The bilayered arrangements are coated with a semi-permeable wall. Thewall forming composition comprises 95% cellulose acetate having a 39.8%acetyl content, and 5% polyethylene glycol having a molecular weight of3350. The wall-forming composition is dissolved in an acetone:water(95:5 wt:wt) cosolvent to make a 4% solids solution. The wall-formingcomposition is sprayed onto and around the bilayers in a 24" Vector Hi®Coater.

Next, two 30 mil (0.762 mm) exit passageways are drilled through thesemi-permeable wall to connect the drug layer with the exterior of thedosage system. The residual solvent is removed by drying for 48 hours at50° C. and 50% humidity. Next, the osmotic dosage forms are dried for 4hours at 50° C. to remove excess moisture. The dosage form produced bythis manufacture provides 28.8% morphine sulfate pentahydrate, 64.2%poly(ethylene oxide) possessing a 200,000 molecular weight, 6%poly(vinyl pyrrolidone) possessing a 40,000 molecular weight, and 1%magnesium stearate. The push composition comprises 63.675% poly(ethyleneoxide) comprising a 7,000,000 molecular weight, 30% sodium chloride, 5%hydroxypropylmethylcellulose comprising a 11,200 molecular weight, 1%ferric oxide, 0.075% butylated hydroxytoluene, and 0.25% magnesiumstearate. The semipermeable wall comprises 95 wt % cellulose acetatecomprising a 39.8% acetyl content, and 5.0 wt % polyethylene glycolcomprising a 3350 molecular weight. The dosage form comprises twopassageways, 30 mils (0.762 mm), and it had a morphine sulfate meanrelease rate of 5 mg/hr.

The dosage form in further embodiments can comprises 65 wt % to 100 wt %of a cellulose polymer which polymer comprises a member selected fromthe group consisting of a cellulose ester, cellulose diester, cellulosetriester, cellulose ether, cellulose ester-ether, cellulose acylate,cellulose diacylate, cellulose triacetate, cellulose acetate butyrate,and the like. The wall can also comprise from 0 wt % to 40 wt % of acellulose ether member selected from the group consisting ofhydroxypropylcellulose and hydroxypropylmethylcellulose and from 0 wt %to 20 wt % of polyethylene glycol. The total amount of all componentscomprising the wall is equal to 100 wt %. Semipermeable polymers usefulfor manufacturing wall of dosage form are disclosed in U.S. Pat. Nos.3,845,770; 3,916,899; 4,008,719; 4,036,228; and 4,111,201. These patentsare assigned to the ALZA Corporation of Palo Alto, Calif., the assigneeof this patent application.

The wall in other preferred manufacture, comprises the selectivelypermeable cellulose ether, ethyl cellulose. The ethyl cellulosecomprises an ethoxy group with a degree of substitution, DS, of about1.4 to 3, equivalent to 40% to 50% ethoxy content, and a viscosity rangeof 7 to 100 centipoise, or higher. More specifically, the wall comprises45 wt % to 80 wt % ethyl cellulose, from 5 wt % to 30 wt %hydroxypropylcellulose, and from 5 wt % to 30 wt % polyethylene glycol,with the total weight percent of all components comprising the wallequal to 100 wt %. In another embodiment the wall comprises 45 wt % to80 wt % of ethylcellulose, from 5 wt % to 30 wt %hydroxypropylcellulose, from 2 wt % to 20 wt % of polyvinyl pyrrolidone,with the total amount of all components comprising the wall equal to 100wt %. The ethylcellulose polymer is known in U.S. Pat. No. 4,519,801assigned to the ALZA Corporation of Palo Alto, Calif.

EXAMPLE 4

In the dosage forms provided by the invention, the drug composition cancomprises 10 to 98 wt % morphine, morphine base, morphine salt, ormorphine derivative; 10 to 80 wt % poly(alkylene oxide) possessing a100,000 to 650,000 molecular weight or 10 to 80 wt % of acarboxymethylcellulose, such as sodium carboxymethylcellulose orpotassium carboxymethylcellulose possessing a 10,000 to 400,000molecular weight; 1 to 20 wt % poly(vinyl pyrrolidone) orhydroxypropylcellulose or hydroxypropylmethylcellulose; and 0.25 to 10wt % lubricant such as magnesium stearate. In the dosage form, the pushcomposition comprises 40 to 99 wt % poly(alkylene oxide) exemplified bypoly(ethylene oxide) comprising a 3,000,000 to 7,750,000 molecularweight, or 20 to 99 wt % of alkali carboxymethylcellulose comprising a500,000 to 1,000,000 molecular weight; 0 to 80 wt % of an osmagent, alsoknown as osmotic effective solute, represented by magnesium sulfate,sodium chloride, lithium chloride, potassium sulfate, sodium sulfate,lithium sulfate, potassium acid phosphate, mannitol, urea, inositol,magnesium succinate, tartaric acid, carbohydrates like raffinose,sucrose, glucose, lactose, fructose, sodium chloride fructose, andpotassium chloride dextrose; and 0.25 to 25 wt % of ahydroxyalkylcellulose selected from the group consisting ofhydroxyethylcellulose, hydroxypropylcellulose,hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxypropylmethylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, which hydroxyalkylcellulose comprises a7,500 to 75,000 molecular weight; 0 to 3 wt % ferric chloride; 0 to 3 wt% antioxidant represented by d-alpha tocopherol, dl-alpha tocopherol,d-alpha tocopherol acetate, dl-alpha-tocopherol acetate, d-alphatocopherol acid succinate, dl-alpha tocopherol acid succinate, ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene, andpropyl gallate; and 0 to 3 wt % lubricant represented by magnesiumstearate, calcium stearate, corn starch, potato starch, bentonite,citrus pulp, and stearic acid; with all ingredients in the pushcomposition equal to 100 wt %, weight percent.

The expression, "exit means," for the dosage form as used, comprisesmeans and methods suitable for the metered release of beneficial drugmorphine from the dosage form. The exit means comprises at least onepassageway, orifice, or the like, through the wall for communicatingwith morphine in the dosage form. The expression, "at least onepassageway," comprises aperture, orifice, bore, pore, porous elementthrough which the drug can migrate, hollow fiber, capillary tube, porousoverlay, porous insert, and the like. The expression also includes amaterial that erodes or is leached from the wall in the fluidenvironment of use to produce least one passageway in the dosage form.Representative materials suitable for forming at least one passageway,or a multiplicity of passageways, include an erodible poly(glycolic)acid, or poly(lactic) acid member in the wall, a gelatinous filament,poly(vinyl alcohol), leachable materials such as fluid removable poreforming polysaccharides, salts, oxides, or the like. A passageway or aplurality of passageways can be formed by leaching a material such assorbitol, lactose, fructose and the like from the wall. The passagewaycan have any shape such as round, triangular, square, elliptical, andthe like, for assisting in the metered release of morphine from thedosage form. The dosage from can be constructed with one or morepassageways in spaced apart relations, or more than one passageway on asingle surface of a dosage form. Passageways and equipment for formingpassageways are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899;4,063,064 and 4,088,864. Passageways of govern size formed by leachingare disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.

Exemplary solvents used for the present purpose comprise inorganic andorganic solvents that do not adversely harm the materials and the finalwall or the final compositions in the dosage form. The solvents broadlyinclude members selected from the group consisting of aqueous solvents,alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenatedsolvents, cycloaliphatics, aromatics, heterocyclic solvents, andmixtures thereof, Typical solvents include acetone, diacetone alcohol,methanol, ethanol, butyl alcohol, methyl acetate, ethyl acetate,isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methylpropyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether,ethylene glycol monoethyl acetate, methylene dichloride, ethylenedichloride, propylene dichloride, carbon tetrachloride, chloroform,nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropylether, cyclo-hexane, cyclo-octane, benzene, toluene, naphtha,1,4-dioxane, tetrahydrofuran, diglyme, aqueous and nonaqueous mixturesthereof, such as acetone and water, acetone and methanol, acetone andethyl alcohol, methylene dichloride and methanol, and ethylenedichloride and methanol.

EXAMPLE 5

Representative of another dosage form provided by this invention is asfollows: first, 116.1 g of morphine sulfate pentahydrate, 81.45 g ofpoly(ethylene oxide) of 200,000 molecular weight, and 81.45 g ofpoly(ethylene oxide) of 300,000 molecular weight were blended in ablender at the lowest speed for 2 minutes. Then, 78 g of poly(vinylpyrrolidone) of 40,000 molecular weight and 500 mL of ethanol wereblended for approximately 1 hour. Then, 126 mL of the poly(vinylpyrrolidone)/ethanol blend was slowly added to the dry ingredients whileblending in the mixer at the lowest speed. The granulation was driedovernight and then passed through a 0.0333", (0.846 mm) screen. Next,2.9 g of magnesium stearate (1% of final granulation) was blended intothe granulation for 1 minute using a mixer at the lowest speed.

Next, 0.7×0.375" (17.8×9.5 mm) oval dosage forms were compressed in apress with a 1 ton compression force. The pressed layers comprised of517 mg of the morphine granulation and 310 mg of a fluid-imbibingexpanding push granulation comprising 197.6 mg of poly(ethylene oxide)having a 7,000,000 molecular weight, 93.0 mg of sodium chloride, 15.5 mgof hydroxypropylmethylcellulose of 11,200 molecular weight, 3.1 mgferric oxide, 0.8 mg of magnesium stearate, and 0.2 mg of butylatedhydroxytoluene.

The push granulation was fluid bed granulated at the 120 kg scale on theGlatt fluid-bed granulator. The binder solution was made by dissolvinghydroxypropylmethylcellulose and butylated hydroxytoluene in water andethanol. This solution was sprayed on the poly(ethylene oxide), sodiumchloride, hydroxypropylmethylcellulose, and ferric oxide blend while theblend was fluidized, and granules were formed. After the granulation isdried, it is milled using a Fluid Air Mill. Finally, the lubricant,magnesium stearate, is added.

The push pull morphine sulfate dosage forms were coated on the 24" HiCoater. Lactose cores, 0.7"×0.375" in size, were used to bring thecoater load up to 10 kg. The components of the semi-permeable membraneare a 95:5 (wt:wt) mixture of cellulose acetate with a 39.8% acetylcontent and polyethylene glycol with a molecular weight of 3350. Thesecomponents are dissolved in a 95:5 (wt:wt) mixture of acetone and waterat 4% solids. An aqueous based coating solution can also be used toapply the semi-permeable membrane to this system. Two 30 mil orificesare drilled into each system. Then, the dosage forms are dried overnightat 37 degrees Celsius to yield the dosage form.

DISCLOSURE FOR USING THE INVENTION

The invention concerns also a method for administering 50 ng to 1,200 mgof morphine to a patient, said method comprising orally admitting intothe patient 50 ng to 1,200 mg of morphine selected from the groupconsisting of morphine and morphine salt, administered from atherapeutic composition comprising 50 ng to 1,200 mg of morphine, 5 mgto 750 mg of a poly(alkylene oxide) having a 100,000 to 650,000molecular weight and 0.5 mg to 80 ng of poly(vinyl pyrrolidone) having a3,000 to 350,000 molecular weight over an extended time.

The method provides additionally administering 50 ng to 1,200 mg ofmorphine, in the patient administered from a dosage form comprising asemipereable wall permeable to aqueous-biological fluid and imperviousdrug; a morphine composition, which dosage form comprises 10 to 98 wt %morphine, 10 to 80 wt % poly(alkylene oxide) possessing a 100,000 to650,000 molecular weight, and 1 to 20 wt % poly(vinyl pyrrolidone), anda push composition compressing 40 to 99 wt % poly(alkylene oxide)comprising a 3,000,000 to 7,750,000 molecular weight, 0 to 80 wt % of anosmagent, and 0.25 to 25 wt % of a hydroxy-alkylcellulose possessing a7,500 to 75,000 molecular weight, which morphine composition and pushcompositions are surrounded by the semipermeable wall; and exit means inthe wall for delivering the morphine from the dosage form, by imbibingfluid through the wall into the dosage from causing the morphinecomposition, and causing the push composition to expand and push themorphine composition through the exit means, whereby through thecombined operations of the dosage form, morphine is delivered at atherapeutically effective dose at a controlled rate over a sustainedperiod of time.

Inasmuch as the forgoing specification comprises disclosed embodiments,it is understand what variations and modifications may be made herein,in accordance with the principles disclosed, without departing from theinvention.

We claim:
 1. A dosage in the form of a tablet comprising: a morphinecomposition layer comprising 10 wt % to 98 wt % of morphine, 10 wt % of80 wt % of a poly(alkylene oxide) having a 100,000 to 650,000 molecularweight, and 1 wt % to 20 wt % of a poly(vinyl pyrrolidone) having a3,000 to 350,000 molecular weight; an expandable layer comprisinggranules coated with hydroxypropylmethylcellulose, said granulescomprising 40 wt % to 99 wt % of poly(alkylene oxide) having a 3,000,000to 7,500,000 molecular weight, 0 wt % to 80 wt % of an osmagent, and0.25 wt % to 25 wt % of hydroxyalkylcellulose having a 7,500 to 75,000molecular weight.
 2. The dosage form according to claim 1, whereinmorphine is a member selected from the group consisting of morphinebase, morphine chlorhydrate, morphine bitartrate, morphinebi(trifluoroacetate), morphine bi(pentafluoropropionate), morphinebi(methylcarbonate), morphine bi(heptafluorbutyrate), morphine phosphatemonobasic, morphine acetate, morphine n-oxide, morphine sulfate,morphine n-oxide, morphine oleate, morphine methylbiomide, morphinemutate, morphine hydrochloride, and morphine hydrobiomide.
 3. A methodfor administering 50 ng to 1,200 mg of morphine to a human, which methodcomprises admitting orally into the gastrointestinal tract of the human50 ng to 1,200 mg of morphine that is administered from a dosage in theform of a tablet comprising a morphine layer comprising 10 wt % to 98 wt% of morphine, 10 wt % to 80 wt % of poly(alkylene oxide) having a100,000 to 650,000 molecular weight and 1 wt % to 20 wt % of poly(vinylpyrrolidone) having a 3,000 to 350,000 molecular weight, a hydrogellayer comprising coated granules comprising 40 wt % to 99 wt % ofpoly(alkylene oxide) having 3,000,000 to 7,500,000 molecular weight, and0 wt % to 80 wt % of an osmagent, said coat comprising 0.25 wt % to 25wt % of a hydroxyalkylcellulose possessing a 7,500 to 75,000 molecularweight, and a semipermeable cellulose acetate polymeric compositionsurrounding the morphine layer and the hydrogel layer.